16.10.2014 - (idw) Max-Delbrck-Centrum fr Molekulare Medizin (MDC) Berlin-Buch

In their search for the earliest possible stage of development of human embryonic stem cells (hESCs) that still have the potential to develop into any types of body cells and tissue, researchers from the Max Delbrck Center for Molecular Medicine (MDC) Berlin-Buch, Germany, and the University of Bath, United Kingdom, have apparently been successful. Jichang Wang, Gangcai Xie, and Dr. Zsuzsanna Izsvk (MDC), together with Professor Laurence D. Hurst (University of Bath), report the discovery of a subtype of cells in culture dishes with hESCs and human induced pluripotent stem cells (hiPSCs) that resemble this very early, pluripotent or nave state (Nature, doi:10.1038/nature13804)*. They also discovered the mechanism that turns human ES cells into nave-like human stem cells. While this has potential implications for medicine and for understanding early human development, an evolutionary enigma still remains unsolved.

Human embryonic stem cells (hESCs) differ considerably from those of mice. Mouse nave cultures resemble the inner cell mass which gives rise to the embryo, while none of the cultured hESC lines do. Nave ESCs of mice are easy to maintain, but not human ESCs isolated from pre-implantation embryos. The hESC lines, researchers work with in their laboratories are considered to be less nave, and have limited differentiation potential. Researchers hypothesize that they have partially lost their pluripotency. Why this is so remains unclear.

What properties characterize human nave stem cells? Can they be identified and proliferated in the laboratory and retained in culture? Researchers in Europe, Asia and the USA are trying to find the answers to these questions in order to be able to use these cells for therapy in the future.

Evolution pointed the way It was evolution that showed the researchers in Bath and Berlin the way to the successful approach. They pinpointed one particular class of ancient viruses called HERVH (human endogenous retrovirus H). HERVH integrated into our DNA millions of years ago, and although it does not function as a virus any longer, it is not silent.

HERVH-derived sequences appear at a very early stage in human embryos, that is, HERVH is highly expressed at just the right time and place in human embryos where one would expect to see nave stem cells. This was also observed by Professor Kazutoshi Takahashi (Kyoto University, Kyoto, Japan), almost at the same time when Dr. Izsvk and Professor Hurst made their discovery.**

Dr. Izsvk and Professor Hurst succeeded in going one step further. They were able to identify the switch that regulates HERVH. In hESC cultures they identified a transcription factor called LBP9 as being central to the activity of HERVH in early embryos. Using a reporter system that made cells expressing HERVH via LBP9 glow green, the Berlin and Bath team found that they had purified human ESCs that showed all the hallmarks of nave mouse stem cells.

This transcription factor was not previously known to be important to human stem cells. However, unknown to them at the time, the same transcription factor was shown by Austin Smiths group (University of Cambridge, UK) to have a role in mouse nave cells***.

Our human nave-like cells look remarkably like the mouse ones, and are close to human inner cell mass (ICM), said Jichang Wang (PhD student, MDC), first author of the Nature publication. With our HERVH-based reporter system we can easily isolate nave-like human ESCs from any human ESC culture. These cells grow like the mouse nave stem cells and express many of the same genes such as NANOG, KLF4 and OCT4 that are associated with murine navet. When we knockdown LBP9 or HERVH, these cells no longer resemble nave-like human stem cells, he added.

To explore a potential role in stem cell-based therapeutics, the next task will be to keep these isolated human nave-like stem cells in culture and proliferate them. HERVH would also be particularly useful in identifying optimal conditions for long-term culturing. As HERVH inhibits differentiation, its expression should be transient, otherwise it might be detrimental to normal embryo development. What factors keep this delicate process in balance is yet to be determined.

Read more:

Researchers in Berlin and Bath Identify Nave-Like Human Stem Cells